The circulation of blood from and to organs guarantees the supply of oxygen, nutrients, as well as the disposal of catabolic products. Therefore, the integrity of blood vessels is essential at all times. When the vascular integrity is compromised, a highly efficient repair mechanism is activated at the site of injury resulting in the formation of a repair seal to prevent further blood loss. This fundamental biological process is defined as hemostasis. Thrombosis is the result of a pathological deviation of one or several components involved in hemostasis leading to uncontrolled platelet thrombus formation and vessel occlusion. Platelets have been described to contribute to hemostasis and thrombosis since their discovery (Coller B S, Historical perspective and future directions in platelet research. J Thromb Haemost. 2011; 9 Suppl 1:374-395). More recently, atherosclerotic lesions in combination with occlusive platelet thrombi have been found in patients with ischemic cardiac death (Davies M J et al., Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation. 1986; 73:418-427).
Inhibition of platelet aggregation is recognized as an effective strategy for the prevention of thrombosis in patients with atherosclerotic disease in the coronary (Jneid H et al., 2012 accf/aha focused update of the guideline for the management of patients with unstable angina/non-st-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): A report of the american college of cardiology foundation/american heart association task force on practice guidelines. J Am Coll Cardiol. 2012; 60:645-681; O'Gara P T et al., 2013 accf/aha guideline for the management of st-elevation myocardial infarction: A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2013; 127:e362-425), peripheral (Jagroop I A et al., The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease. Platelets. 2004; 15:117-125; Matsagas M et al., The effect of a loading dose (300 mg) of clopidogrel on platelet function in patients with peripheral arterial disease. Clin Appl Thromb Hemost. 2003; 9:115-120), and cerebrovascular circulation (Liu F et al., P2Y12 receptor inhibitors for secondary prevention of ischemic stroke. Expert Opin Pharmacother. 2015; 16:1149-1165). Inhibition of P2Y12 as an antiplatelet approach was validated in multiple clinical studies. Several P2Y12 antagonists have been demonstrated to effectively reduce the risk of adverse cardiovascular events in patients with acute coronary syndromes (ACS) and patients undergoing percutaneous coronary intervention (PCI) (Cattaneo M, The platelet P2Y12 receptor for adenosine diphosphate: Congenital and drug-induced defects. Blood. 2011; 117:2102-2112; Thomas M R et al., The future of P2Y12 receptor antagonists. Platelets. 2015; 26:392-398; Wiviott S D et al., Clinical evidence for oral antiplatelet therapy in acute coronary syndromes. Lancet. 2015; 386:292-302; Wallentin L, P2Y12 inhibitors: Differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J. 2009; 30:1964-1977). In current treatment guidelines, P2Y12 antagonists define the cornerstone therapy for patients with ACS (Jneid H et al., 2012 accf/aha focused update of the guideline for the management of patients with unstable angina/non-st-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): A report of the american college of cardiology foundation/american heart association task force on practice guidelines. J Am Coll Cardiol. 2012; 60:645-681; O'Gara P T et al., 2013 accf/aha guideline for the management of st-elevation myocardial infarction: A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2013; 127:e362-425).
Three indirect P2Y12 antagonists of the thienopyridine family, which block the ADP-induced platelet activation and aggregation, have reached the market: the orally active ticlopidine, clopidogrel and prasugrel. In addition, two direct P2Y12 antagonists, which do not require metabolic activation and therefore display faster on- and offset of action, have received market approval: the nucleotide analogues ticagrelor and cangrelor. 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester is a potent, reversible, and selective P2Y12 receptor antagonist (Caroff E et al., J. Med. Chem. 2015; 58:9133-9153; WO 2009/069100). Its hydrochloride salt was used as a powder in a first-in-man clinical trial (Baldoni et al., Clinical Drug Investigation 2014; 34:807-818).
Despite the fact that many attempts failed to crystallize COMPOUND.HCl from several solvents in a mono-phase solvent system, it surprisingly has been found that a crystallization took place in certain heterogeneous solvent systems. The obtained crystalline forms of COMPOUND.HCl may have advantageous properties in view of the potential use of COMPOUND.HCl or COMPOUND as active pharmaceutical ingredient. Such advantages may include higher purity; better storage stability; better flow properties; less hygroscopicity; better reproducibility in manufacturing (for example better filtration parameters, better reproducibility of formation, and/or better sedimentation); and/or defined morphology. Such crystalline forms of COMPOUND.HCl may be particularly suitable in a process of manufacturing certain pharmaceutical compositions.
In the gravimetric vapour sorption diagrams of FIGS. 4, 5, and 6 the relative humidity (% RH) is plotted on the horizontal axis and the mass change (% dm, dry basis) on the vertical axis.